Summary Constitutive activation mutations of BRAF account for majority of cutaneous melanoma, which activatethemitogen-activatedproteinkinase(MAPK)pathway,promotingtumorigenesis.While inhibitors for BRAF, alone or in combination with MEK inhibitors, have shown good initial responses, resistant tumors occur eventually, representing a major challenge in melanoma therapy.RecentstudiesindicatethatYAP,thetranscriptionco-activatorsoftheHippopathway, plays important roles in the development of resistance to MAPK-blockade (MAPKi) in melanoma. YAP interacts with TEAD transcriptional factors to drive oncogenic transcriptional programs that are important for cancer cell growth, survival, epithelial-mesenchymal transition and regulation of immune response, such as recruitment of immunosuppressive Myeloid- derivedsuppressorcells(MDSCs).Wehaverecentlydevelopednovelsmallmoleculeinhibitors ofTEADs(MGH-CP1anditsanalogues)thattargetTEADauto-palmitoylation,disrupttheYAP- TEAD interaction and inhibit their transcriptional activities. Moreover, we have found that the levels of TEADs and MDSC-attracting cytokine CXCL6, a transcriptional target of YAP, are upregulated in MAPKi-resistant melanoma cells, compared to their MAPKi-sensitive counterparts.Basedonthestrongscientificpremiseandourpreliminaryresults,wehypothesize that targeting the YAP-TEAD transactivation activity with TEAD inhibitors is an effective therapeutic strategy for MAPKi-resistant melanomas;? and that TEAD upregulation and YAP- dependent recruitment of MDSCs to tumor microenvironment play important role in the development MAPKi resistance in melanomas. The overall goal of the proposal is to understand the role of YAP-TEAD signaling in MAPKi-resistant melanoma and to develop therapeuticstrategiestocombatMAPKiresistance.Inaim1,wewillinvestigatethecontribution of TEAD upregulation to the development of MAPKi-resistance in melanoma. In aim 2, we will evaluatetheeffectsofsmallmoleculeinhibitorsofTEADsinMAPKiresistantmelanomasusing both cell culture and animal models. In aim 3, we will elucidate the contribution of YAP- dependentMDSCinfiltrationtothedevelopmentofMAPKiresistanceinmelanoma.